HTLV-1 has been linked to the development of adult T cell leukemia (ATL) and a neurological disorder termed HAM/TSP. Limitations in the understanding of fundamental mechanisms of leukemogenesis by HTLV have predominantly been hampered by the lack of an animal model which recapitulates pathogenesis. HTLV-1 infects human hematopoietic progenitor and stem (CD34+) cells (HPCs and HSCs, respectively) and inoculation of NOD/SCID mice with infected CD34+ cells results in human hematolymphopoiesis and dissemination of viral infection to mature human T cells and monocytes. HTLV-1 infection and Tax1 expression in CD34+ HSCs may play a role in maintenance of viral latency, sequestration of virus and in dissemination of HTLV infection during differentiation in vivo. We postulate that HTLV-1 infected CD34+ cells in the BM serve as a reservoir for viral infection in vivo and that Tax1 expression in these cells initiates mutagenic events which manifest in development of ATL. The newly-developed NOD- scid IL2R-null mouse will be used to characterize the kinetics of HTLV replication in vivo and determine if infection results in leukemogenesis. Lentiviral vector (LV) mediated transduction of Tax1 into human CD34+ cells will evaluate the role of this viral oncoprotein on T lymphopoiesis in NOD-scid IL2R-null hu mice. We propose to evaluate HTLV-infected cell subpopulations for mutations in tumor suppressor genes commonly associated with ATL development. Our unique combination of expertise will allow us to develop a novel paradigm to examine the molecular events in hematopoietic stem cells induced by HTLV infection and Tax expression which contributes to virally-mediated leukemogenesis. Specific Aims are: Aim 1: Characterize HTLV infection, replication tropism and leukemogenesis following reconstitution of human hematopoiesis in NOD-scid IL2R-null mice with HTLV-1 infected CD34+ HPCs. Establish if HTLV-1 infection perturbs hematopoiesis in vivo and induces leukemogenesis. Determine whether mutations in tumor suppressor genes occur in lymphoproliferations arising from infected HTLV-infected hematopoietic stem and progenitor cells are similar to those in ATL patients. Aim 2: Examine the role of Tax1 and Tax2 on T lymphopoiesis using lentivirus vector (LV) -mediated transduction of CD34+ HPCs and reconstitution of hematopoiesis in the NOD- scid IL2R-null -hu mouse model. Aim 3: Investigate infection of the NOD-scid IL2R-null -hu mouse using infectious recombinant proviral clones of HTLV-1 and HTLV-2 containing the heterologous Tax genes. Determine the replication kinetics and pathogenesis of HTLV HBZ in vivo. Human T cell leukemia virus (HTLV) causes Adult T cell leukemia (ATL) and a neurological disorder termed HAM/TSP. We speculate that HTLV infects human stem cells and predisposes cells to become leukemogenic, resulting in an infected "cancer stem cell". Modeling HTLV infection in an immune deficient mouse which supports the development of human lymphocytes will allow us to define molecular events induced by HTLV infection in human stem cells which result in leukemia. [unreadable] [unreadable] [unreadable]